A reader sent along a note about this letter to Nature Medicine earlier in the year. It’s about drug repurposing, and more specifically about the Drug Repurposing Hub at the Broad Institute. This is a collection of nearly 5,000 compounds, curated and annotated with their histories and activities. It was not a straightforward task:
. . .we sought to assemble a comprehensive library of drugs that have reached the clinic. Surprisingly, we found that no such chemical library of approved and clinical trial drugs is available for purchase. In particular, drugs that have been tested in clinical trials but did not reach approval are not readily accessible. Even obtaining a complete list of such drugs and their annotations is challenging. A prior effort led by the US National Institutes of Health (NIH) focused on drugs approved by the US Food and Drug Administration (FDA), but the library has few compounds that have yet to achieve FDA approval7. Some chemical vendors offer a subset of approved drugs, but most of these commercial libraries overlap in their content and include only a small fraction of the approximately 10,000 drugs that have reached the clinic in the United States and Europe. Given that no complete collection exists, we launched a three-step effort to create the Repurposing Library by (i) identifying and purchasing compounds; (ii) comprehensively annotating their known activities and clinical indications; and (iii) experimentally confirming drug identity and purity.
This looks like a very useful resource, and I’m glad to bring it up. But there’s one aspect of its creation that I wanted to highlight, which is what caught my correspondent’s eye. Intensive combing of databases showed that about 10,000 different small-molecule drugs have reached clinical development over the years. Fewer than 6,000 of these are commercially available substances, but the team purchased them all, and from multiple vendors when possible.
Outside of all the functional and historical annotation of these compounds, there’s the question of whether they are what they’re advertised to be. And here’s the part to note:
The final step in creating a drug-screening library is experimental confirmation of compound identity and purity. We therefore tested all compound samples in the Repurposing Library by ultra-performance liquid chromatography–mass spectrometry (UPLC–MS), after receipt of the compound from the vendor. Surprisingly, 2,482 of 8,584 samples (29%) failed QC, defined as a purity of less than 85%, as measured by UPLC absorbance peak area at 210 nm, or by an evaporative light-scattering detector (ELSD) for peaks containing the expected compound mass (Supplementary Fig. 4a). The majority of QC failures were subsequently confirmed by the vendors of the compounds upon checking of the source stocks.
Readers will vary in whether or not they are surprised by that. I would have been stunned if they’d reported that everything came back fine, but 29% is probably still a bit higher than I would have guessed (the last time I worked through a big list of purchased compounds, I think we lost about 20%). It appears that many of these QC failures came about through compound storage in DMSO, but not all of them can be blamed on that. In total, 984 compounds had to be excluded from the collection, even though they were putatively commercially available, because there was no source for them with material that passed analysis.
Experienced compound-library users already know this – but this should serve as a warning: don’t trust what’s on the label. Always run a check before you commit a purchased compound to your assays. Always check them again every time one hits from your own archive – it may have been just what it says on the label back in 2004, but it may not be now. When it comes to compound identity and purity, it’s strictly Nullius in verba – on no one’s word – or you’ll come to regret it.